Generation Of Toxic Products Research Articles

Understanding Why Post-Stroke Depression May Be the Norm Rather Than the Exception: The Anatomical and Neuroinflammatory Correlates of Post-Stroke Depression.

Ischemic Stroke precedes depression. Post-stroke depression (PSD) is a major driver for poor recovery, negative quality of life, poor rehabilitation outcomes and poor functional ability. In this systematic review, we analysed the inflammatory basis of post-stroke depression, which involves bioenergetic failure, deranged iron homeostasis (calcium influx, Na influx, potassium efflux etc), excitotoxicity, acidotoxicity, disruption of the blood brain barrier, cytokine-mediated cytotoxicity, reactive oxygen mediated toxicity, activation of cyclooxygenase pathway and generation of toxic products. This process subsequently results in cell death, maladapted, persistent neuro-inflammation and deranged neuronal networks in mood-related brain regions. Furthermore, an in-depth review likewise reveals that anatomic structures related to post-stroke depression may be localized to complex circuitries involving the cortical and subcortical regions.

Insight into the generation of toxic products during chloramination of carbamazepine: Kinetics, transformation pathway and toxicity

As a widely used antiepileptic drug, carbamazepine (CBZ) has been frequently detected in aquatic environments, even in drinking water. Chloramine is a widely used alternative disinfectant due to its low-level formation of regulated disinfection byproducts (DBPs). However, there is previous evidence linking product mixtures of chloraminated CBZ to stronger DNA damage effects than those caused by CBZ itself. The present study further investigated the reaction rate, transformation mechanism and multi-endpoint toxicity of transformation products (TPs) of CBZ treated with NH2Cl under different pH conditions. The results showed that the reaction between CBZ and NH2Cl at pH 8.5, where NH2Cl is stable, is a second-order reaction with a rate of 4.2 M−1 h−1. Compared to both alkaline and acidic conditions, CBZ was quickly degraded at pH 7. This indicated that HOCl produced from NH2Cl hydrolysis is more effective in degrading CBZ than NH2Cl and NHCl2. Furthermore, the concentration variation of four TPs formed during the chloramination of CBZ under different pH conditions was investigate by quantitative analysis, and the transformation pathway from CBZ to 9(10H)-acridone was confirmed. Three of the detected TPs showed cytotoxicity, DNA damage effects or chromosome damage effects. Acridine and 9(10H)-acridone, which accumulated with increasing time, showed higher cytotoxic or genotoxic effects than CBZ itself. In addition, a similar transformation mechanism was observed in real ambient water during simulated chloramination with a low level of CBZ. These results suggested that despite the chloramination of CBZ being slower than chlorination, TPs with higher cytotoxicity or genotoxicity may lead to greater toxic risks.

300. Changing the Route of Administration to Improve Liver Transduction by Recombinant AAV-Based Vectors

The liver is a central organ in metabolism and there are numerous inherited metabolic disorders that have their origin in this organ. Gene therapy represents a promising therapeutic approach for this type of diseases. Although in preclinical studies using AAV-based vectors high and long-term hepatic expression has been achieved, there are still some concerns about the expression levels and the percentage of hepatocytes that can be transduced. This is of particular importance for diseases in which the deficiency of an enzymatic activity is associated with the generation of toxic products that require the transduction of a high percentage of hepatocytes. Therefore, the main goal of our study was to improve liver transduction efficacy by an AAV serotype. For this purpose, the vector was administered directly to the liver via suprahepatic veins (SHV) using a catheter and balloon occlusion or via the hepatic artery (HA) with balloon occlusion of the suprahepatic vein. The experiment was performed in Macaca fascicularis, with 8 animals being infected with a dose of 3×1013 gc/kg of an AAV5 expressing the reporter gene hSEAP (human secreted embryonic alkaline phosphatase) under the control of a liver specific promoter (AAV5-AAT-hSEAP). The first group (2 animal) received the virus systemically in the saphenous vein, the second group (3 animals) received the virus via the SHV with 10 minutes of balloon occlusion and the third group (3 animals) via the HA with 10 minutes of balloon occlusion of the SHV. The procedure could only be performed on the right branch of SHV and HA due to the small size of the left SHV and HA branches, reaching only 40% of the liver. hSEAP-specific activity in serum samples of the groups that received the virus directly in the hepatic blood flow was higher compared to the animals receiving the vector by peripheral intravenous injection. This was correlated with the presence of a higher number of viral genomes in the liver of the animals. Moreover, when their distribution was analyzed we found that the animals that had received the virus through the SHV or HA displayed higher infection rates in the right side of the liver, where the administration had been performed. In conclusion, direct administration of the vector AAV5-AAT-hSEAP through the hepatic blood flow with balloon occlusion was associated with higher transgene expression and an increase in vector genomes in the injected area. Studies in bigger animals in order to reach both sides of the liver should be performed in order to explore the potential use of alternative routes of administration in the clinic.

Green chemistry, sustainable agriculture and processing systems: a Brazilian overview

Abstract There is a pressing need for renewable and optimal use of resources towards sustainable primary production and processing systems worldwide. Current technologies for food and feedstock production are held accountable for several environmental problems, such as for instance soil and water contamination due to the use of hazardous substances, generation of toxic products and even excess of biomass that is considered waste. To minimize or solve these questions in order to produce an adequate quantity of reliable and healthy food, fibers and other products and energy, new paradigms focusing on sustainable agriculture, bio-based industries or biorefineries have emerged over the last decades. Biorefineries integrate sustainable and environmentally friendly concepts of Green Chemistry with intelligent and integrated farming processes, optimizing the agricultural production. Thermochemical and biochemical processes are excellent alternatives for the production of new classes of renewable biofuels and feedstock, showing relatively small impact on greenhouse gas emissions and important pathways to obtain platform chemicals. This review discusses the current and incipient technological developments for using biomass to generate bio-based chemicals over the last decade, focusing on Green Chemistry concepts towards sustainable agriculture and processing models in Brazil.

The basis of the immunomodulatory activity of malaria pigment (hemozoin)

The most common and deadly form of the malaria parasite, Plasmodium falciparum, is responsible for 1.5-2.7 million deaths and 300-500 million acute illnesses annually [Bremen in J. Trop. Med. Hyg. 64:1-11 (2001); World Health Organization (2002)]. Hemozoin, the biomineral formed to detoxify the free heme produced during parasitic hemoglobin catabolism, has long been suspected of contributing to the pathological immunodeficiencies that occur during malarial infection. While there is a growing consensus in the literature that native hemozoin maintains immunosuppressive activity, there is considerable controversy over the reactivity of the synthetic form, beta-hematin (BH). Given the emerging importance of hemozoin in modulating a host immune response to malarial infection, a careful examination of the effects of the constitutive components of the malaria pigment on macrophage response has been made in order to clarify the understanding of this process. Herein, we present evidence that BH alone is unable to inhibit stimulation of NADPH oxidase and inducible nitric oxide synthase, the key enzymes involved in oxidative burst, and is sensitive to the microbicidal agents of these enzymes both in vitro and in vivo. Further, by systematically examining each of the malaria pigment's components, we were able to dissect their impact on the immune reactivity of a macrophage model cell line. Reactions between BH and red blood cell (RBC) ghosts effectively reconstituted the observed immunomodulatory reactivity of native hemozoin. Together, these results suggest that the interaction between hemozoin and the RBC lipids results in the generation of toxic products and that these products are responsible for disrupting macrophage function in vivo.

Effect of dietary resistant starch and protein on colonic fermentation and intestinal tumourigenesis in rats

Protein as well as starch is fermented in the colon, but the interaction between protein and starch fermentation and the impact on colonic oncogenesis is unknown. High-protein diets increase delivery of protein to the colon and might promote oncogenesis through generation of toxic products. We investigated the interaction of resistant starch (RS) with digestion-resistant potato protein (PP) on colonic fermentation events and their relationship to intestinal tumourigenesis. Male Sprague-Dawley rats were fed an AIN-76A-based diet for 4 weeks and intestinal neoplasms were induced by azoxymethane. Experimental diets included the following: no added RS or PP, 10% high amylose maize starch (source of RS) replacing digestible starch, 15% PP replacing casein and 10% high amylose maize starch+15% PP. Rats were maintained on diets until killed at 30 weeks. Feeding RS significantly increased short-chain fatty acid (SCFA) levels (P<0.001) in the caecum and colon. Importantly, butyrate concentration was significantly increased in the distal colon with RS (P<0.001). Feeding PP increased protein fermentation products, but this effect was reduced by adding RS to the diet. Intestinal neoplasms and colorectal adenocarcinomas were reduced by feeding RS (P<0.01) regardless of whether PP was fed, whereas PP alone increased the incidence and number of small intestinal neoplasms including the adenocarcinomas (P<0.01). In conclusion, RS altered the colonic luminal environment by increasing the concentration of SCFAs including butyrate and lowering production of potentially toxic protein fermentation products. These effects of RS not only protected against intestinal tumourigenesis but also ameliorated the tumour-enhancing effects of feeding indigestible protein.

Effects of lipid peroxidation products on the rat lens in organ culture: A possible mechanism of cataract initiation in retinal degenerative disease

Rat lenses in organ culture which are exposed to bovine rod outer segments (ROS) or to the major fatty acid of ROS, docosahexaenoic acid, are impaired in their ability to accumulate radiolabeled compounds which lenses normally accumulate by active processes. The extent of lens damage correlates well with the extent of lipid peroxidation in the culture medium as assessed by the thiobarbituric acid assay. Addition of vitamin E to the medium inhibits the effect on the lens while addition of Fe-ADP complexes potentiates the effect. Thus, the lens damage appears to be attributable to toxic species generated by peroxidation of the polyunsaturated lipid added to the culture medium. Toxic aldehyde products appear to be major mediators of the lens damage, since semi-carbazide, which avidly reacts with aldehydes, can protect lenses in this system. These findings may have relevance to the cataracts clinically associated with retinal degenerative diseases such as retinitis pigmentosa. The highly membranous photoreceptor cells are extremely rich in polyunsaturated lipid. Degeneration of these cells, which is the primary pathology in such diseases, would likely lead to peroxidation with generation of toxic products within the eye. Such products could potentially produce secondary damage to other ocular structures including the lens.